U.S. patent application number 10/510668 was filed with the patent office on 2006-11-02 for carboximide derivatives as useful uro-selective alpha-1a adrenoceptor blockers.
Invention is credited to Nitya Anand, Anita Chugh, Jang Bahadur Gupta, Gobind Singh Kapkoti, Mohammad Salman, Somesh Sharma, Gyan Chand Yadav.
Application Number | 20060247249 10/510668 |
Document ID | / |
Family ID | 37235267 |
Filed Date | 2006-11-02 |
United States Patent
Application |
20060247249 |
Kind Code |
A1 |
Salman; Mohammad ; et
al. |
November 2, 2006 |
Carboximide derivatives as useful uro-selective alpha-1a
adrenoceptor blockers
Abstract
Novel carboximide derivatives, which selectively inhibit binding
to the .alpha..sub.1A adrenergic receptor, a receptor which has
been shown to be important in the treatment of benign prostatic
hyperplasia. The compounds of the present invention are potentially
useful in the treatment of benign prostatic hyperplasia.
Inventors: |
Salman; Mohammad; (Haryana
Gurgaon, IN) ; Yadav; Gyan Chand; (Uttar Pradesh
Ghaziabad, IN) ; Sharma; Somesh; (New Delhi, IN)
; Kapkoti; Gobind Singh; (Gurgaon, IN) ; Chugh;
Anita; (New Delhi, IN) ; Gupta; Jang Bahadur;
(Gurgaon, IN) ; Anand; Nitya; (Lucknow,
IN) |
Correspondence
Address: |
RANBAXY INC.
600 COLLEGE ROAD EAST
SUITE 2100
PRINCETON
NJ
08540
US
|
Family ID: |
37235267 |
Appl. No.: |
10/510668 |
Filed: |
November 16, 2005 |
PCT NO: |
PCT/IB02/01108 |
Current U.S.
Class: |
514/252.13 ;
514/254.11; 514/389; 544/374; 544/375; 548/311.1 |
Current CPC
Class: |
C07D 241/04 20130101;
C07D 295/32 20130101; C07D 405/12 20130101; C07D 295/13
20130101 |
Class at
Publication: |
514/252.13 ;
514/254.11; 514/389; 544/374; 544/375; 548/311.1 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 31/4178 20060101 A61K031/4178; C07D 405/02
20060101 C07D405/02; C07D 409/02 20060101 C07D409/02 |
Claims
1. A compound having the structure of Formula I, ##STR9## and its
pharmaceutically acceptable salts, enantiomers, diastereomers,
N-oxides, prodrugs, metabolities, polymorphs, or pharmaceutically
acceptable solvates, wherein X is selected from the group
consisting of ##STR10## wherein the points of attachment are
depicted by hashed bonds, and wherein one point of attachment is
bonded to the carbonyl adjacent to the nitrogen and the second
point of attachment is bonded to the other carbonyl; W is O, S, SO
or SO.sub.2; A is --(CH.sub.2)m--, ##STR11## wherein m is one of
the integers 2, 3 or 4; R.sub.11 is independently selected from H,
F, Cl, Br, I, OH, straight or branched lower (C.sub.1-6) alkyl,
lower (C.sub.1-6) alkoxy and lower (C.sub.1-6) perhaloalkyl; Y is
selected from the group consisting of ##STR12## R.sub.1 and R.sub.2
are independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
OR.sub.3,COR.sub.3, OCOR.sub.3, COOR.sub.3, NH.sub.2, N(R.sub.4,
R.sub.5), lower (C.sub.1-4)alkyl, lower (C.sub.1-4) alkoxy, lower
(C.sub.1-4)alkylthio, lower (C.sub.1-4)perhaloalkyl, lower
(C.sub.1-4) perhaloalkoxy, lower (C.sub.1-4)alkoxy substituted with
one or more of F, Cl, Br, I, OH, or OR.sub.3, optionally
substituted group selected from aryl, aryloxy, aralalkyl,
heterocyclyl or heteroaryl and said substituents being H, F, Cl,
Br, I, OH, OR.sub.3, lower (C.sub.1-4)alkyl, lower (C.sub.1-4)alkyl
substitued with one or more of F, Cl, Br, I, OH or OR.sub.3,
wherein R.sub.3 is selected from the group consisting of H straight
or branched C.sub.1-C.sub.6 alkyl and perhaloalkyl; R.sub.4 and
R.sub.5 are independently selected from the group consisting of H,
CHO, substituted or unsubstituted lower (C.sub.1-4)alkyl, lower
(C.sub.1-4)alkoxy, COR.sub.3, COOR.sub.3,
CH.sub.2CH(OR.sub.3).sub.2, CH.sub.2COOR.sub.3, CH.sub.2CHO and
(CH.sub.2).sub.2OR.sub.3 wherein R.sub.3 is the same as defined
above; R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
straight or branched lower (C.sub.1-4)alkyl optionally substituted
with one or more halogens, lower (C.sub.1-4)alkoxy optionally
substituted with one or more halogens, (C.sub.3-8)cycloalkoxy,
NH.sub.2, N-lower(C.sub.1-4)alkylamino, N,N-di-lower
(C.sub.1-C.sub.4)alkylamino, N-lower alkyl(C.sub.1-C.sub.4)amino
carbonyl, hydroxy substituted with aromatic or non-aromatic five or
six membered ring, phenyl, phenyl substitued by Cl, F, Br, I,
NO.sub.2, NH.sub.2, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
(C.sub.1-4)perhaloalkyl, (C.sub.1-4)perhaloalkoxy wherein a broken
line (....) is a single bond or no bond.
2. A compound selected from the group consisting of
1-Carboxy-cyclohex-4-ene-2-[N-{3-(2-ethoxyphenyl)piperazin-1-yl)propyl]ca-
rboxamide;
1-Carboxy-cyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}propy-
l]carboxamide; 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-methoxyphenyl)piperazin-1-yl}-2-hydroxypropyl]c-
arboxamide; 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}-2-hydroxypropyl]c-
arboxamide; 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}-2-hydroxy
propyl]carboxamide; 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-ethoxyphenyl)piperazin-1yl}-2-hydroxyphenyl]car-
boxamide;
5-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}]-1-aminopropyl-5-oxo-p-
entan-1-oic acid; 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}propyl]carboxamide-
;
5-[N-{3-(2-Isopropoxyphenyl)piperazin-1-yl}-1-aminopropyl]-5-oxo-pentan-
-1-oic acid;
Methyl-5-[N-{3-(2-methoxyphenyl)piperazin-1-yl}-1-aminopropyl]-5-oxo-pent-
anoate hydrochloride;
1-Carboxymethylcyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}-
-propyl]carboxamide hydrochloride;
5-[N-{3-(2-Methoxyphenyl)piperazin-1-yl}]-2-hydroxypropylamino-5-oxo-pent-
an-1-oic acid.
3. A method of selectively antagonizing .alpha..sub.1-adrenergic
receptors in a mammal comprising administering to said mammal a
therapeutically effective amount of a compound having the structure
of Formula I: ##STR13## and its pharmaceutically acceptable salts,
enantiomers, diastereomers, N-oxides, prodrugs, metabolities,
polymorphs, or pharmaceutically acceptable solvates, wherein X is
selected from the group consisting of ##STR14## wherein the points
of attachment are depicted by hashed bonds, and wherein one point
of attachment is bonded to the carbonyl adjacent to the nitrogen
and the second point of attachment is bonded to the other carbonyl;
W is O, S, SO or SO.sub.2; A is --(CH.sub.2)m--, ##STR15## wherein
m is one of the integers 2, 3 or 4; R.sub.11 is independently
selected from H, F, Cl, Br, I, OH, straight or branched lower
(C.sub.1-6) alkyl, lower (C.sub.1-6) alkoxy and lower (C.sub.1-6)
perhaloalkyl; Y is selected from the group consisting of ##STR16##
R.sub.1 and R.sub.2 are independently selected from H, OH, CN,
NO.sub.2, Cl, F. Br, I, OR.sub.3,COR.sub.3, OCOR.sub.3, COOR.sub.3,
NH.sub.2, N(R.sub.4, R.sub.15), lower (C.sub.1-4)alkyl, lower
(C.sub.1-4) alkoxy, lower (C.sub.1-4)alkylthio, lower
(C.sub.1-4)perhaloalkyl, lower (C.sub.1-4)perhaloalkoxy, lower
(C.sub.1-4)alkoxy substituted with one or more of F, Cl, Br, I, OH,
or OR.sub.3, optionally substituted group selected from aryl,
aryloxy, aralalkyl, heterocyclyl or heteroaryl and said
substituents being H, F, Cl, Br, I, OH, OR.sub.3, lower
(C.sub.1-4)alkyl, lower (C.sub.1-4)alkyl substitued with one or
more of F, Cl, Br, I, OH or OR.sub.3, wherein R.sub.3 is selected
from the group consisting of H, straight or branched
C.sub.1-C.sub.6 alkyl and perhaloalkyl; R.sub.4 and R.sub.5 are
independently selected from the group consisting of H, CHO,
substituted or unsubstituted lower (C.sub.1-4)alkyl, lower
(C.sub.1-4)alkoxy, COR.sub.3, COOR.sub.3,
CH.sub.2CH(OR.sub.3).sub.2, CH.sub.2COOR.sub.3, CH.sub.2CHO and
(CH.sub.2).sub.2OR.sub.3 wherein R.sub.3 is the same as defined
above; R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
straight or branched lower (C.sub.1-4)alkyl optionally substituted
with one or more halogens, lower (C.sub.1-4)alkoxy optionally
substituted with one or more halogens, (C.sub.3-6)cycloalkoxy,
NH.sub.2, N-lower(C.sub.1-4)alkylamino, N,N-di-lower
(C.sub.1-C.sub.4)alkylamino, N-lower alkyl(C.sub.1-C.sub.4)amino
carbonyl, hydroxy substituted with aromatic or non-aromatic five or
six membered ring, phenyl, phenyl substitued by Cl, F, Br, I,
NO.sub.2, NH.sub.2, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
(C.sub.1-4)perhaloalkyl, (C.sub.1-4)perhaloalkoxy wherein a broken
line (....) is a single bond or no bond.
4. A method for treating benign prostatic hyperplasia in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound having the structure of Formula I: ##STR17##
and its pharmaceutically acceptable salts, enantiomers,
diastereomers, N-oxides, prodrugs, metabolities, polymorphs, or
pharmaceutically acceptable solvates, wherein X is selected from
the group consisting of ##STR18## wherein the points of attachment
are depicted by hashed bonds, and wherein one point of attachment
is bonded to the carbonyl adjacent to the nitrogen and the second
point of attachment is bonded to the other carbonyl; W is O, S, SO
or SO.sub.2; A is --(CH.sub.2)m--, ##STR19## wherein m is one of
the integers 2, 3 or 4; R.sub.11 is independently selected from H,
F, Cl, Br, I, OH, straight or branched lower (C.sub.1-6) alkyl,
lower (C.sub.1-6) alkoxy and lower (C.sub.1-6) perhaloalkyl; Y is
selected from the group consisting of ##STR20## R.sub.1 and R.sub.2
are independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
OR.sub.3,COR.sub.3, OCOR.sub.3, COOR.sub.3, NH.sub.2, N(R.sub.4,
R.sub.5), lower (C.sub.1-4)alkyl, lower (C.sub.1-4) alkoxy, lower
(C.sub.1-4)alkylthio, lower (C.sub.1-4)perhaloalkyl, lower
(C.sub.1-4)perhaloalkoxy, lower (C.sub.1-4)alkoxy substituted with
one or more of F, Cl, Br, I, OH, or OR.sub.3, optionally
substituted group selected from aryl, aryloxy, aralalkyl,
heterocyclyl or heteroaryl and said substituents being H, F, Cl,
Br, I, OH, OR.sub.3, lower (C.sub.1-4)alkyl, lower (C.sub.1-4)alkyl
substitued with one or more of F, Cl, Br, I, OH or OR.sub.3,
wherein R.sub.3 is selected from the group consisting of H,
straight or branched C.sub.1-C.sub.6 alkyl and perhaloalkyl;
R.sub.4 and R.sub.5 are independently selected from the group
consisting of H, CHO, substituted or unsubstituted lower
(C.sub.1-4)alkyl, lower (C.sub.1-4)alkoxy, COR.sub.3, COOR.sub.3,
CH.sub.2CH(OR.sub.3).sub.2, CH.sub.2COOR.sub.3, CH.sub.2CHO and
(CH.sub.2).sub.2OR.sub.3 wherein R.sub.3 is the same as defined
above; R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
straight or branched lower (C.sub.1-4)alkyl optionally substituted
with one or more halogens, lower (C.sub.1-4)alkoxy optionally
substituted with one or more halogens, (C.sub.3-6)cycloalkoxy,
NH.sub.2, N-lower(C.sub.1-4)alkylamino, N,N-di-lower
(C.sub.1-C.sub.4)alkylamino, N-lower alkyl(C.sub.1-C.sub.4)amino
carbonyl, hydroxy substituted with aromatic or non-aromatic five or
six membered ring, phenyl, phenyl substitued by Cl, F, Br, I,
NO.sub.2, NH.sub.2, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
(C.sub.1-4)perhaloalkyl, (C.sub.1-4)perhaloalkoxy wherein a broken
line (....) is a single bond or no bond.
5. A pharmaceutical composition comprising a therapeutically
effective amount of a compound as defined in claim 1 or 2 and a
pharmaceutical acceptable carrier.
6. A method of selectively antagonizing .alpha..sub.1-adrenergic
receptors in a mammal comprising the step of administering to said
mammal a therapeutically effective amount of the pharmaceutical
composition according to claim 5.
7. A method for treating benign benign prostatic hyperplasia in a
mammal comprising the step of administering to said mammal a
therapeutically effective amount of the pharmaceutical composition
according to claim 5.
8. A process for preparing a compound of Formula I ##STR21## or its
pharmaceutically acceptable salts, enantiomers, diastereomers,
N-oxides, prodrgus, metabolities, polymorphs, and pharmaceutically
acceptable solvates wherein X is selected from the group consisting
of ##STR22## wherein the points of attachment are depicted by
hashed bonds, and wherein one point of attachment is bonded to the
carbonyl adjacent to the nitrogen and the second point of
attachment is bonded to the other carbonyl; W is O, S, SO or
SO.sub.2; A is --(CH.sub.2)m--, ##STR23## wherein m is one of the
integers 2, 3 or 4; R.sub.11 is independently selected from H, F,
Cl, Br, I, OH, straight or branched lower (C.sub.1-6) alkyl, lower
(C.sub.1-6) alkoxy and lower (C.sub.1-6) perhaloalkyl; Y is
selected from the group consisting of ##STR24## R.sub.1 and R.sub.2
are independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
OR.sub.3,COR.sub.3, OCOR.sub.3, COOR.sub.3, NH.sub.2, N(R.sub.4,
R.sub.5), lower (C.sub.1-4)alkyl, lower (C.sub.1-4) alkoxy, lower
(C.sub.1-4)alkylthio, lower (C.sub.1-4)perhaloalkyl, lower
(C.sub.1-4) perhaloalkoxy, lower (C.sub.1-4)alkoxy substituted with
one or more of F, Cl, Br, I, OH, or OR.sub.3, optionally
substituted group selected from aryl, aryloxy, aralalkyl,
heterocyclyl or heteroaryl and said substituents being H, F, Cl,
Br, I, OH, OR.sub.3, lower (C.sub.1-4)alkyl, lower (C.sub.1-4)alkyl
substitued with one or more of F, Cl, Br, I, OH or OR.sub.3,
wherein R.sub.3 is selected from the group consisting of H,
straight or branched C.sub.1-C.sub.6 alkyl and perhaloalkyl;
R.sub.4 and R.sub.5 are independently selected from the group
consisting of H, CHO, substituted or unsubstituted lower
(C.sub.1-4)alkyl, lower (C.sub.1-4)alkoxy, COR.sub.3, COOR.sub.3,
CH.sub.2CH(OR.sub.3).sub.2, CH.sub.2COOR.sub.3, CH.sub.2CHO and
(CH.sub.2).sub.2OR.sub.3 wherein R.sub.3 is the same as defined
above; R.sub.6, R.sub.7, R.sub.8, R.sub.10 and R.sub.10 are
independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
straight or branched lower (C.sub.1-4)alkyl optionally substituted
with one or more halogens, lower (C.sub.1-4)alkoxy optionally
substituted with one or more halogens, (C.sub.3-6)cycloalkoxy,
##STR25## NH.sub.2, N-lower(C.sub.1-4)alkylamino, N,N-di-lower
(C.sub.1-C.sub.4)alkylamino, N-lower alkyl(C.sub.1-C.sub.4)amino
carbonyl, hydroxy substituted with aromatic or non-aromatic five or
six membered ring, phenyl, phenyl substitued by Cl, F, Br, I,
NO.sub.2, NH.sub.2, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
(C.sub.1-4)perhaloalkyl, (C.sub.1-4)perhaloalkoxy wherein a broken
line (....) is a single bond or no bond; which comprises reacting a
compound Formula II with a suitable base in a suitable solvent to
give the compound of Formula I as shown below: where all symbols
are as defined above.
9. The process of claim 8 wherein the base is selected from the
group consisting of potassium hydroxide and sodium hydroxide.
10. The process of claim 8 wherein the suitable solvent is selected
from the group consisting of water, methanol and ethanol.
Description
FIELD OF THE INVENTION
[0001] This invention relates to certain novel carboximide
derivatives which selectively inhibit binding to the .alpha..sub.1A
adrenergic receptor, a receptor which has been shown to be
important in the treatment of benign prostatic hyperplasia. The
compounds of the present invention are potentially useful in the
treatment of benign prostatic hyperplasia. This invention also
relates to methods for synthesizing the novel compounds,
pharmaceutical compositions containing the compounds, and method of
treating benign prostatic hyperplasia using the compounds.
BACKGROUND OF THE INVENTION
[0002] Benign prostatic hyperplasia (BPH), a nonmalignant
enlargement of the prostate, is the most common benign tumor in
men. Approximately 50% of all men older than 65 years have some
degree of BPH and a third of these men have clinical symptoms
consistent with bladder outlet obstruction (Hieble and Caine, Fed.
Proc., 1986; 45:2601). Worldwide benign and malignant diseases of
the prostate are responsible for more surgery than diseases of any
other organ in men over the age of fifty.
[0003] It is generally accepted that there are two components of
BPH, a static and a dynamic component. The static component is due
to enlargement of the prostate gland, which may result in
compression of the urethra and obstruction to the flow of urine
from the bladder. The dynamic component is due to increased smooth
muscle tone of the bladder neck and the prostate itself (which
interferes with emptying of the bladder) and is regulated by alpha
1 adrenergic receptors (.alpha..sub.1-ARs). The medical treatments
available for BPH address these components to varying degrees, and
the therapeutic choices are expanding.
[0004] Surgical treatment options address the static component of
BPH and include transurethral resection of the prostate (TURP),
open prostatectomy, balloon dilatation, hyperthermia, stents and
laser ablation. Although, TURP is the gold standard treatment for
patients with BPH, approximately 20-25% of patients do not have a
satisfactory long--term outcome (Lepor and Rigaud, J. Urol., 1990;
143:533). Postoperative urinary tract infection (5-10%), some
degree of urinary incontinence (2-4%), as also reoperation (15-20%)
(Wennberg et al., JAMA, 1987; 257:933) are some of the other risk
factors involved.
[0005] Apart from surgical approaches, there are some drug
therapies which address the static component of this condition.
Finasteride (Proscar, Merck), is one such therapy which is
indicated for the treatment of symptomatic BPH. This drug is a
competitive inhibitor of the enzyme 5.alpha.-reductase which is
responsible for the conversion of testosterone to
dihydrotestosterone in the prostate gland (Gormley et al., N. Engl.
J. Med., 1992; 327:1185). Dihydrotestosterone appears to be the
major mitogen for prostate growth, and agents which inhibit
5-.alpha.-reductase reduce the size of the prostate and improve
urine flow through the prostatic urethra. Although finasteride is a
potent 5.alpha.-reductase inhibitor and causes a marked decrease in
serum and tissue concentration of dihydrotestosterone, it is only
moderately effective in treating symptomatic BPH (Oesterling, N.
Engl. J. Med., 1995; 332:99). The effects of finasteride take 6-12
months to become evident and for many men the clinical improvement
is minimal.
[0006] Due to the limited effectiveness of 5.alpha.-reductase
inhibitors in terms of immediate symptomatic and urodynamic relief,
other pharmacological approaches have been assessed in the clinical
setting.
[0007] The dynamic component of BPH has been addressed by the use
of adrenergic receptor blocking agents (.alpha..sub.1-AR blockers)
which act by decreasing the smooth muscle tone within the prostate
gland itself. .alpha..sub.1-adrenergic receptor antagonists appear
to be much more effective and provide immediate subjective
symptomatic improvements and are, therefore, the preferred
modalities of treatment in the control of benign prostate
hypertrophy. .alpha..sub.1-Adrenoceptors are also present in blood
vessels and play an important role in the regulation of blood
pressure. Thus, .alpha..sub.1-adrenoceptor antagonists are of
particular importance as they were originally developed as
antihypertensive agents and are likely also to have a beneficial
affect on lipid dysfunction and insulin resistance, which are
commonly associated with essential hypertension.
[0008] The use of .alpha..sub.1-AR antagonists in the treatment of
BPH is related to their ability to decrease the tone of prostatic
smooth muscle, leading to relief of the obstructive symptoms.
Adrenergic receptors found throughout the body play a dominant role
in the control of blood pressure, nasal congestion, prostate
function and other processes (Harrison et al., Trends Pharmacol.
Sci., 1991; 12:62). There are a number of cloned .alpha..sub.1-AR
receptor subtypes: .alpha..sub.1A-AR, .alpha..sub.1B-AR and
.alpha..sub.1D-AR (Bruno et al., Biochem. Biophys. Res. Commun.,
1991; 179:1485; Forray et al., Mol. Pharmacol., 1994; 45:703;
Hirasawa et al., Biochem. Biophys. Res. Commun., 1993; 195:902;
Ramarao et al., J. Biol. Chem., 1992; 267:21936; Schwinn et al.,
JPET, 1995; 272:134; Weinberg et al., Biochem. Biophys. Res.
Commun., 1994; 201:1296). A number of laboratories have
characterized the .alpha..sub.1-ARS in human prostate by function,
radioligand binding, and molecular biological techniques (Forray et
al., Mol. Pharmacol. 1994; 45:703; Hatano et al., Br. J. Pharmacol,
1994; 113:723; Marshall et al., Br. J. Pharmacol. 1992; 112:59;
Marshall et al., Br. J. Pharmacol., 1995; 115:781; Yamada et al.,
Life Sci., 1994; 54:1845). These studies provide evidence in
support of the concept that the .alpha..sub.1A-AR subtype comprises
the majority of .alpha..sub.1-ARS in human prostatic smooth muscle
and mediates contraction in this tissue. These findings suggest
that the development of a subtype-selective .alpha..sub.1A-AR
antagonists might result in a therapeutically effective agent with
reduced side effects for the treatment of BPH.
[0009] A variety of .alpha..sub.1-AR blockers (terazosin, prazosin,
and doxazosin) have been investigated for the treatment of
symptomatic bladder outlet obstruction due to BPH, with terazosin
(Hytrin, Abbott) being the most extensively studied. Although the
.alpha..sub.1-AR blockers are well tolerated, approximately 10-15%
of patients develop a clinically adverse event. The undesirable
effects of all members of this class are similar, with postural
hypotension being the most commonly experienced side effect.
[0010] The .alpha..sub.1-AR blocking agents have a more rapid onset
of action. However, their therapeutic effect, as measured by
improvement in the symptom score and the peak urinary flow rate, is
moderate. (Oesterling, N. Engl. J. Med., 1995; 332:99). The
vascular side effects (e.g., postural hypertension, dizziness,
headaches, etc.) associated with these drugs is due to lack of
selectivity of action between prostatic and vascular
.alpha..sub.1-adrenoceptors. Clearly, .alpha..sub.1-adrenoceptor
antagonists which have inherently greater selectivity for prostatic
.alpha..sub.1-adrenoceptors offer the potential of increased
urodynamic benefits. This underscores the importance of the
discovery of prostate-selective .alpha..sub.1-adrenoceptor
antagonists which will confer urodynamic improvement without the
side effects associated with existing drugs.
[0011] There are many description in the literature about the
pharmacological activities associated with
.alpha.,.omega.-dicarboximide derivatives. Eur. J. Med. Chem.
Chemica Therapeutica; 1977; 12(2):173, J. Indian. Chem. Soc., 1978;
LV:819; J. Indian Chem. Soc., 1979; LVI:1002 discuss the synthesis
of these derivatives with CNS and antihypertensive activity. Other
references like U.S. Pat. Nos. 4,524,206; 4,598,078; 4,567,180;
4,479,954; 5,183,819; 4,748,240; 4,892,943; 4,797,488; 4,804,751;
4,824,999; 4,957,913; 5,420,278; 5,330,762; 4,543,355 and PCT
application Nos. WO 98/37893; WO 93/21179, also describe CNS and
antihypertensive activity of these compounds. There is no mention
of adrenoceptor blocking activity of these compounds and thus their
usefulness in the treatment of BPH did not arise.
[0012] J. Med. Chem., 1983; 26:203 reports dopamine and
.alpha..sub.1-adrenergic activity of some Buspirone analogues. EP
078800 discusses .alpha..sub.1-adrenergic receptor antagonistic
activity of pyrimidinedione, pyrimidinetrione and triazinedione
derivatives. These compounds, however, had low
.alpha..sub.1-adrenergic blocking activity as compared to known
.alpha..sub.1-antagonists.
[0013] The earlier synthesis of various
1-(4-arylpiperazin-1-yl)-3-(2-oxo-pyrrolidin-1-yl/piperidin-1-yl)alkanes
and their usefulness as hypotensive and antischemic agents is
disclosed in Indian Patent applications 496/DEU95, 500/DEU95 and
96/DEU96. These compounds had low .alpha..sub.1-adrenergic blocking
activity (pKi.about.6 as compared to >8 of the known
.alpha..sub.1-antagonists such as prazosin), and practically no
adrenoceptor sub-class selectivity for .alpha..sub.1A vs.
.alpha..sub.1B or .alpha..sub.1D adrenoceptors. Further work showed
that structural modification of these compounds from lactam to
dioxo compounds, i.e., from 2-oxopyrrolidin to 2,5-dioxopyrrolidin
and 2,6-dioxopiperidine, enhances the adrenoceptor blocking
activity, and also greatly increases the selectivity for
.alpha..sub.1A in comparison to .alpha..sub.1B-adrenoceptor
blocking activity, an essential requirement for compounds to be
good candidates for treatment of benign prostatic hyperplasia (BPH)
disclosed in our U.S. Pat. Nos. 6,083,950 and 6,090,809 which are
incorporated herein by reference.
OBJECTS OF THE INVENTION
[0014] Recently, it has been demonstrated that the prostate tissue
of higher species like man and dog has a predominant concentration
of .alpha..sub.1A-adrenoceptor subtype. This makes it possible to
develop agents with selective action against these pathological
urodynamic states. The present invention is directed to the
development of novel .alpha..sub.1-adrenoceptors and which would
thus offer a viable selective relief for prostate hypertrophy as
well as essential hypertension, without the side effects associated
with known .alpha..sub.1A-AR antagonists.
[0015] The objective of the present invention is to provide novel
carboximide derivatives that exhibit significantly greater
.alpha..sub.1A-adrenergic blocking potency than available with
known compounds in order to provide specific treatment for benign
prostatic hyperplasia.
[0016] It is also an object of the invention to provide a process
for synthesis of the novel compounds.
[0017] It is a further object of the invention to provide
compositions containing the novel compounds which are useful in the
treatment of benign prostatic hyperplasia.
SUMMARY OF THE INVENTION
[0018] The above mentioned objectives are achieved by novel
carboximide derivatives represented by Formula I below:
##STR1##
[0019] wherein X is selected from the group consisting of
##STR2##
[0020] where the points of attachment are depicted by hashed bonds,
and
[0021] where one point of attachment is bonded to the carbonyl
adjacent to the nitrogen and the second point of attachment is
bonded to the other carbonyl;
W is O, S, SO or SO.sub.2
[0022] A is --(CH.sub.2)m--, ##STR3##
[0023] where m is one of the integers 2, 3 or 4;
[0024] R.sub.11 is independently selected from H, F, Cl, Br, I, OH,
straight or branched lower (C.sub.1-6) alkyl, lower (C.sub.1-6)
alkoxy, lower (C.sub.1-6) perhaloalkyl and lower (C.sub.1-6)
perhaloalkoxy;
[0025] Y is selected from the group consisting of ##STR4##
[0026] R.sub.1 and R.sub.2 are independently selected from H, OH,
CN, NO.sub.2, Cl, F, Br, I, OR.sub.3, COR.sub.3, OCOR.sub.3,
COOR.sub.3, NH.sub.2, N(R.sub.4, R.sub.15), lower (C.sub.1-4)alkyl,
lower (C.sub.1-4)alkoxy, lower (C.sub.1-4)alkylthio, lower
(C.sub.1-4) perhaloalkyl, lower (C.sub.1-4) perhaloalkoxy, lower
(C.sub.1-4) alkoxy substituted with one or more of F, Cl, Br, I,
OH, or OR.sub.3, optionally substituted group selected from aryl,
aryloxyaralkyl, heterocyclyl or heteroaryl and said substituents
being H, F, Cl, Br, I, OH, OR.sub.3, lower (C.sub.1-4)alkyl, lower
(C.sub.1-4)alkyl substitued with one or more of F, Cl, Br, I, OH or
OR.sub.3, wherein R.sub.3 is selected from the group consisting of
H, straight or branched C.sub.1-C.sub.6 alkyl and perhaloalkyl;
R.sub.4 and R.sub.5 are independently selected from the group
consisting of H, CHO, substituted or unsubstituted lower
(C.sub.1-4)alkyl, lower (C.sub.1-4)alkoxy, COR.sub.3, COOR.sub.3,
CH.sub.2CH(OR.sub.3).sub.2, CH.sub.2COOR.sub.3, CH.sub.2CHO and
(CH.sub.2).sub.2OR.sub.3 where R.sub.3 is the same as defined
above; R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
straight or branched lower (C.sub.1-4)alkyl optionally substituted
with one or more halogens, lower (C.sub.1-4)alkoxy optionally
substituted with one or more halogens, (C.sub.3-6)cycloalkoxy,
NH.sub.2, N-lower (C.sub.1-4)alkylamino, N,N-di-lower
(C.sub.1-C.sub.4)alkylamino, N-lower (C.sub.1-C.sub.4) alkyl amino
carbonyl, hydroxy substituted with aromatic or non-aromatic five or
six membered ring, phenyl and phenyl substituted by Cl, F, Br, I,
NO.sub.2, NH.sub.2, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
(C.sub.1-4) perhaloalkyl, (C.sub.1-4) perhaloalkoxy wherein a
broken line (----) is a single bond or no bond.
[0027] The present invention also provides pharmaceutical
compositions for the treatment of benign prostatic hyperplasia.
These compositions comprise an effective amount of at least one of
the above compounds of Formula I and/or an effective amount of at
least one physiologically acceptable acid addition salt thereof,
with a pharmaceutically acceptable carrier and optionally included
excipients.
[0028] An illustrative list of particular compounds of the
invention is given below: [0029]
1-Carboxycyclohex-4-ene-2-[N-{3-(2-ethoxyphenyl)piperazin-1-yl}propyl]car-
boxamide, (Compound No. 1) [0030] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}propyl]carboxam-
ide, (Compound No. 2) [0031] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-methoxyphenyl)piperazin-1-yl}-2-hydroxypropyl]c-
arboxamide, (Compound No. 3) [0032] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}-2-hydroxypropyl]c-
arboxamide, (Compound No. 4) [0033] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}-2-hydroxypropy-
l]carboxamide, (Compound No. 5) [0034] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-ethoxyphenyl)piperazin-1yl}-2-hydroxyphenyl]car-
boxamide, (Compound No. 6) [0035]
5-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}]-1-aminopropyl-5-oxo-pentan-1-oi-
c acid, (Compound No. 7) [0036] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}propyl]carboxamide-
, (Compound No. 8) [0037]
5-[N-{3-(2-Isopropoxyphenyl)piperazin-1-yl}-1-aminopropyl]-5-oxo-pentan-1-
-oic acid, (Compound No. 9) [0038]
Methyl-5-[N-{3-(2-methoxyphenyl)piperazin-1-yl}-1-aminopropyl]-5-oxo-pent-
anoate hydrochloride, (Compound No. 10) [0039]
1-Carboxymethylcyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}-
-propyl]carboxamide hydrochloride, (Compound No. 11) [0040]
5-[N-{3-(2-Methoxyphenyl)piperazin-1-yl}]-2-hydroxypropylamino-5-oxo-pent-
an-1-oic acid, (Compound No. 12)
[0041] Pharmaceutically acceptable, non-toxic acid addition salts
of the compounds of the present invention having the utility of the
free bases of Formula I, may be formed with inorganic or organic
acids, by methods well known in the art and may be used in place of
the free bases. Representative examples of suitable acids for
formation of such acid addition salts are malic, fumaric, benzoic,
ascorbic, pamoic, succinic, bismethylene salicylic,
methanesulfonic, ethane disulfonic, acetic, propionic, tartaric,
salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic,
glycolic, p-aminobenzoic, glutamic, benzenesulfamic, phosphoric,
hydrobromic, sulfuric, cyclohexylsulfamic, hydrochloric, and nitric
acids.
[0042] The present invention also includes within its scope
prodrugs of the compounds of Formula I. In general, such prodrugs
will be functional derivatives of these compounds which readily get
converted in vivo into the defined compounds. Conventional
procedures for the selection and preparation of suitable prodrugs
are known.
[0043] The invention also includes the enantiomers, diastereomers,
N-oxides, polymorphs, pharmaceutically acceptable salts and
pharmaceutically acceptable solvates of these compounds, as well as
metabolites having the same type of activity. The invention further
includes pharmaceutical compositions comprising the molecules of
Formula I, or prodrugs, metabolites, enantiomers, diastereomers,
N-oxides, polymorphs, solvates or pharmaceutically acceptable salts
thereof, in combination with a pharmaceutically acceptable carrier
and optionally included excipients.
[0044] In yet another aspect, the invention is directed to methods
for selectively blocking .alpha..sub.1A receptors by delivering in
the environment of said receptors, e.g., to the extracellular
medium (or by administering to a mammal possessing said receptors),
an effective amount of the compounds of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0045] In order to achieve the above mentioned objects and in
accordance with the purpose of the invention as embodied and
broadly described herein, there is provided a process for the
synthesis of compounds of Formula I, as shown in Scheme I
##STR5##
[0046] wherein X is selected from the group consisting of
##STR6##
[0047] where the points of attachment are depicted by hashed bonds,
and
[0048] where one point of attachment is bonded to the carbonyl
adjacent to the nitrogen and the second point of attachment is
bonded to the other carbonyl;
W is O, S, SO or SO.sub.2
[0049] A is --(CH.sub.2)m--, ##STR7##
[0050] where m is one of the integers 2, 3 or 4;
[0051] R.sub.11 is independently selected from H, F, Cl, Br, I, OH,
straight or branched lower (C.sub.1-6) alkyl, lower (C.sub.1-6)
alkoxy, lower (C.sub.1-6) perhaloalkyl and lower (C.sub.1-6)
perhaloalkoxy;
[0052] Y is selected from the group consisting of ##STR8##
[0053] R.sub.1 and R.sub.2 are independently selected from H, OH,
CN, NO.sub.2, Cl, F, Br, I, OR.sub.3, COR.sub.3, OCOR.sub.3,
COOR.sub.3, NH.sub.2, N(R.sub.4, R.sub.5), lower (C.sub.1-4)alkyl,
lower (C.sub.1-4)alkoxy, lower (C.sub.1-4)alkylthio, lower
(C.sub.1-4) perhaloalkyl, lower (C.sub.1-4) perhaloalkoxy, lower
(C.sub.1-4) alkoxy substituted with one or more of F, Cl, Br, I,
OH, or OR.sub.3, optionally substituted group selected from aryl,
aryloxyaralkyl, heterocyclyl or heteroaryl and said substituents
being H, F, Cl, Br, I, OH, OR.sub.3, lower (C.sub.1-4)alkyl, lower
(C.sub.1-4)alkyl substitued with one or more of F, Cl, Br, I, OH or
OR.sub.3, wherein R.sub.3 is selected from the group consisting of
H, straight or branched C.sub.1-C.sub.6 alkyl and perhaloalkyl;
R.sub.4 and R.sub.5 are independently selected from the group
consisting of H, CHO, substituted or unsubstituted lower
(C.sub.1-4)alkyl, lower (C.sub.1-4)alkoxy, COR.sub.3, COOR.sub.3,
CH.sub.2CH(OR.sub.3).sub.2, CH.sub.2COOR.sub.3, CH.sub.2CHO and
(CH.sub.2).sub.2OR.sub.3 where R.sub.3 is the same as defined
above; R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are
independently selected from H, OH, CN, NO.sub.2, Cl, F, Br, I,
straight or branched lower (C.sub.1-4)alkyl optionally substituted
with one or more halogens, lower (C.sub.1-4)alkoxy optionally
substituted with one or more halogens, (C.sub.3-6)cycloalkoxy,
NH.sub.2, N-lower (C.sub.1-4)alkylamino, N,N-di-lower
(C.sub.1-C.sub.4)alkylamino, N-lower (C.sub.1-C.sub.4) alkyl amino
carbonyl, hydroxy substituted with aromatic or non-aromatic five or
six membered ring, phenyl and phenyl substituted by Cl, F, Br, I,
NO.sub.2, NH.sub.2, (C.sub.1-4)alkyl or (C.sub.1-4)alkoxy,
(C.sub.1-4) perhaloalkyl, (C.sub.1-4) perhaloalkoxy wherein a
broken line (----) is a single bond or no bond.
[0054] The starting materials of Scheme I may be suitably adapted
to produce the more specific compounds of Formula I.
SCHEME I
[0055] Scheme I shows the synthesis of the compounds of Formula I
wherein X, Y, A, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10
are as defined above. The preparation comprises reacting
.alpha.,.omega.-dicarboximides of Formula II with a suitable strong
base, at a temperature ranging from 20-100.degree. C. for a period
varying between one to several hours to produce the corresponding
compounds of Formula I. The suitable base is selected from the
group consisting of sodium hydroxide and potassium hydroxide. More
specifically, the hydrolysis of compound of Formula II is carried
out in a solution of the base made in a polar solvent selected from
the group consisting of water, methanol and ethanol. The preferable
temperature conditions for the reaction are 90-100.degree. C. The
starting compound of Formula II can be prepared by the process as
disclosed in our internal application number RLL-236WO filed
concurrently herewith.
[0056] The invention is explained in detail in the example given
below which is provided by way of illustration only and therefore
should not be construed to limit the scope of the present
invention.
EXAMPLE
Preparation of 1-carboxy
cyclohex-4-ene-2-[N-{3-(2-ethoxyphenyl)piperazin-1-yl}propyl]carboxamide
(Compound No. 1).
[0057]
2-[3-{4-(2-Ethoxyphenyl)piperazin-1-yl}propyl-3a,4,7,7a-tetrahydro-
-1H-isoindole-1,3(2H)-dione hydrochloride (0.5 g, 1.15 mmol) was
dissolved in aqueous sodium hydroxide solution (11.5 ml, 0.2N) and
heated to reflux for about 2 hours. After the reaction was over,
the pH of the reaction was adjusted to about 7 using glacial acetic
acid and extracted with chloroform (2.times.15 ml). The solvent was
concentrated under reduced pressure and the crude product was
crystallized from chloroform and diethylether to afford the title
product 0.13 g (25%), m.pt. 128-131.degree. C.
MS m/z: 430.5 (MH.sup.+)
[0058] IR (KBr cm.sup.-1): 1645.8 (C=0)
[0059] .sup.1H NMR (300 MHz, TFA) .delta.:1.72-1.74 (3H,d), 2.59
(2H, br s), 2.80 (3H, br s), 2.93-2.99 (1H, d), 3.53 (1H, br s),
3.69 (1H, br s), 3.86-3.98 (m, 4H), 4.47-4.50 (6H, m), 4.75-4.79
(2H, m), 5.11-5.19 (1H, m), 6.00-6.13 (2H, br d), 7.39-7.49 (2H,
m), 7.82-7.88 (2H, m)
[0060] The following compounds were prepared similarly: [0061]
1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}propy-
l]carboxamide; m.p. 186-188.degree. C., (Compound NO. 2) [0062]
1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-methoxyphenyl)piperazin-1-yl}-2-hydro-
xypropyl]carboxamide; m.p. 140-143.degree. C., (Compound No. 3)
[0063] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}-2-hydro-
xypropyl]carboxamide; m.p. 124-127.degree. C., (Compound No. 4)
[0064] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}-2-hy-
droxy propyl]carboxamide; m.p. 159-162.degree. C., (Compound No. 5)
[0065] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-ethoxyphenyl)piperazin-1yl}-2-hydroxyphenyl]car-
boxamide; m.p. 118-121.degree. C., (Compound No. 6) [0066]
5-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}]-1-aminopropyl-5-oxo-pentan-1-oi-
c acid; m.p. 200-202.degree. C., (Compound No. 7) [0067] 1-Carboxy
cyclohex-4-ene-2-[N-{3-(2-hydroxyphenyl)piperazin-1-yl}propyl]carboxamide-
; m.p. 165-170.degree. C., (Compound No. 8) [0068]
5-[N-{3-(2-Isopropoxyphenyl)piperazin-1-yl}-1-aminopropyl]-5-oxo-pentan-1-
-oic acid; m.p. 121-125.degree. C., (Compound No. 9) [0069]
Methyl-5-[N-{3-(2-methoxyphenyl)piperazin-1-yl}-1-aminopropyl]-5-oxo-pent-
anoate hydrochloride; m.p. 191-194.degree. C., (Compound No. 10)
[0070]
1-Carboxymethylcyclohex-4-ene-2-[N-{3-(2-isopropoxyphenyl)piperazin-1-yl}-
-propyl]carboxamide hydrochloride, (Compound No. 11) [0071]
5-[N-{3-(2-Methoxyphenyl)piperazin-1-yl}]-2-hydroxypropylamino-5-oxo-pent-
an-1-oic acid; m.p. 140-144.degree. C., (Compound No. 12
Pharmacological Testing Results
[0071] Receptor Binding Assays
[0072] Receptor binding assays were performed using native
.alpha.-adrenoceptors. The affinity of different compounds for
.alpha..sub.1A and .alpha..sub.1B adrenoceptor subtypes was
evaluated by studying their ability to displace specific [.sup.3H]
prazosin binding from the membranes of rat submaxillary and liver
respectively (Michel et al, Br J. Pharmacol.; 1989; 98:883). The
binding assays were performed according to U'Prichard et al. (Eur J
Pharmacol., 1978; 50:87) with minor modifications.
[0073] Submaxillary glands were isolated immediately after
sacrifice. The liver was perfused with buffer (Tris HCl 50 mM, NaCl
100 mM, 10 mM EDTA pH 7.4). The tissues were homogenised in 10
volumes of buffer (Tris HCl 50 mM, NaCl 100 mM, 10 mM EDTA pH 7.4).
The homogenate was filtered through two layers of wet gauge and
filtrate was centrifuged at 500 g for 10 min. The supernatant was
subsequently centrifuged at 40,000 g for 45 min. The pellet thus
obtained was resuspended in the same volume of assay buffer (Tris
HCl 50 mM, 5 mM EDTA pH 7.4) and were stored at -70.degree. C.
until the time of assay.
[0074] The membrane homogenates (150-250 .mu.g protein) were
incubated in 250 .mu.l of assay buffer (Tris HCl 50 mM, EDTA 5 mM,
pH 7.4) at 24-25.degree. C. for 1 hour. Non specific binding was
determined in the presence of 300 nM prazosin. The incubation was
terminated by vacuum filtration over GF/B fibre filters. The
filters were then washed with ice cold 50 mM Tris HCl buffer (pH
7.4). The filtermats were dried and bound radioacivity retained on
filters was counted. The IC.sub.50 and Kd were estimated by using
the non linear curve fitting program using G Pad Prism software.
The value of inhibition constant Ki was calculated from competitive
binding studies by using Cheng & Prusoff equation (Cheng &
Prusoff, Biochem Pharmacol, 1973,22: 3099), Ki=IC.sub.50/(1+L/Kd)
where L is the concentration of [.sup.3H] prazosin used in the
particular experiment (Table I).
In Vitro Functional Studies
[0075] In order to study selectivity of action of these compounds
towards different .alpha.-adrenoceptor subtypes, the ability of
these compounds to antagonise aorta (.alpha..sub.1D), prostate
(.alpha..sub.1A) and spleen (.alpha..sub.1B) was studied. Aorta,
prostrate and spleen tissues were isolated from urethane
anaesthetized (1.5 g/kg) male wister rats. Isolated tissues were
mounted in organ bath containing Krebs Henseleit buffer of the
following composition (mM): NaCl 118; KCl 4.7; CaCl.sub.2 2.5;
MgSO.sub.4 7H.sub.2O 1.2; NaHCO.sub.3 25; KH.sub.2PO.sub.4 1.2;
glucose 11.5. Buffer was maintained at 37.degree. C. and aereated
with a mixture of 95% O.sub.2 and 5% CO.sub.2. A resting tension of
2 g (aorta) or 1 g (spleen and prostate) was applied to tissues.
Contractile response was monitored using a force displacement
transducer and recorded on chart recorders. Tissues were allowed to
equilibrate for 2 hours. At the end of equilibration period,
concentration response curves to norepinephrine (aorta) and
phenylepinephrine (spleen and prostate) were obtained in the
absence and presence of tested compound (at concentration of 0.1, 1
and 10 .mu.M). Antagonist affinity was calculated and expressed as
pK.sub.B values in Table II.
In Vivo Uroselectivity Study
[0076] In order to assess the uroselectivity in vivo, the effects
of these compounds were studied on mean arterial pressure (MAP) and
intraurethral pressure (IUP) in conscious beagle dogs as per the
method of Brune et. al. (Pharmacol., 1996, 53:356). Briefly, male
dogs were instrumented for chronic continuous measurement of
arterial blood pressure by implanting a telemetry transmitter (TL11
M2-D70-PCT, Data Sci. International, St. Paul, Minn. USA) into the
femoral artery, two weeks prior to the study. During the recovery
period, the animal was acclimatized to stay in the sling restraint.
On the day of testing, overnight fasted animal was placed in the
sling restraint. A Swan-Ganz. Balloon tipped catheter was
introduced into the urethra at the level of prostate and the
balloon was inflated (Brune. et. al. 1996). After recording the
base line readings, effect of 16 .mu.g/kg, phenylephrine (i.v.) on
MAP and IUP was recorded. The response of phenylephrine to MAP and
IUP were recorded at 0.5, 1, 2, 3, 4, 6, 9 and 24 hours after the
oral administration of vehicle or the test drug. The changes in MAP
were recorded on line using Dataquest Software (Data Sci.
International. St. Paul, Minn. USA). The change in phenylephrine
response on MAP and IUP administration after the test drug
administration was calculated as percent change of that of control
values. Area under curve was calculated and the ratio of the values
for MAP and IUP was used for calculating the uroselectivity.
TABLE-US-00001 TABLE1 Radioligand Binding Studies: Affinity of
compounds for Alpha-1 Adrenoceptor Subtypes .alpha..sub.1A
.alpha..sub.1B S No Compound No. (Rat Submaxillary) (Rat Liver)
.alpha..sub.1B/.alpha..sub.1A 1 1 20 >1000 >50 2 2 19
>1000 >53 3 3 >1000 >1000 4 4 1892 9743 5 5 5 21 1759
84 6 6 398 1239 3 7 7 12640 12970 1 8 8 593 5082 9 9 9 777 2097 3
10 10 139 >1000 >7 11 11 3.15 99 31 12 12 >1000 >10000
1
[0077] TABLE-US-00002 TABLE II In Vitro Functional Assays
.alpha.-Adrenoceptor Subtype Compound (pK.sub.B) Selectivity S. No.
No. .alpha..sub.1A .alpha..sub.1B .alpha..sub.1D
.alpha..sub.1B/.alpha..sub.1A .alpha..sub.1D/.alpha..sub.1A 1 1
8.22 8.16 7.24 1.15 9.5
[0078] While the present invention has been described in terms of
its specific embodiments, certain modifications and equivalents
will be apparent to those skilled in the art and are intended to be
included within the scope of the present invention.
* * * * *